The Noonday Demon

by Solomon, Andrew

  It is important not to suppress your feelings altogether when you are depressed. It is equally important to avoid terrible arguments or expressions of outrage. You should steer clear of emotionally damaging behavior. People forgive, but it is best not to stir things up to the point at which forgiveness is required. When you are depressed, you need the love of other people, and yet depression fosters actions that destroy that love. Depressed people often stick pins into their own life rafts. The conscious mind can intervene. One is not helpless. A fairly short time after I had snapped out of my third depression, I had dinner with my father and he said something that upset me, and I heard my voice go shrill and my words grow sharp and I was very much alarmed. I could see the trace of recoil in my father. I breathed deeply, and after a pregnant pause, I said, “I’m sorry. I promised not to yell at you and not to be manipulative about these things, and I’m sorry I did it.” This sounds rather namby-pamby, but the ability to intervene consciously does in fact make an enormous difference. A snappy friend once said to me, “For two hundred dollars an hour, you’d think my psychiatrist could go change my family and leave me alone.” Unfortunately, it doesn’t work that way.

  Though CBT and IPT have many specific strengths, any therapy is only as good as the practitioner. Your therapist matters more than your choice of therapeutic system. Someone to whom you connect profoundly can probably help you a lot just by chatting with you in an unstructured environment; someone to whom you do not connect will not really help you no matter how sophisticated his technique or how numerous his qualifications. The key things are intelligence and insight: the format in which that insight is communicated, and the type of insight that is used, are really secondary. In an important study done in 1979, researchers demonstrated that any form of therapy could be effective if certain criteria were met: that both the therapist and the patient were acting in good faith; that the client believed that the therapist understood the technique; and that the client liked and respected the therapist; and that the therapist had an ability to form understanding relationships. The experimenters chose English professors with this quality of human understanding and found that, on average, the English professors were able to help their patients as much as the professional therapists.

  “Mind cannot exist without the brain, but mind can have influence on the brain. It’s a pragmatic and metaphysical problem whose biology we do not understand,” says Elliot Valenstein, professor emeritus of psychology and neuroscience at the University of Michigan. The experiential can be used to affect the physical. As James Ballenger of the Medical University of South Carolina says, “Psychotherapy changes biology. Behavior therapy changes the biology of the brain—probably in the same way the medicines do.” Certain cognitive therapies that are effective for anxiety lower levels of brain metabolism while, in mirror image, pharmaceutical therapies lower levels of anxiety. This is the principle of antidepressant medication, which by modifying the levels of certain substances in the brain changes the way a patient feels and acts.

  Most of the things that go on in the brain during a breakdown are still inaccessible to external manipulation. Research on medical cures for depression has focused tightly on affecting neurotransmitters, mostly because we are able to affect neurotransmitters. Since scientists know that lowering the levels of certain neurotransmitters can cause depression, they work on the assumption that raising levels of these same neurotransmitters can alleviate depression—and indeed drugs that raise levels of neurotransmitters are in many instances effective antidepressants. It is comforting to think that we know the relationship between neurotransmitters and mood, but we don’t. It appears to be an indirect mechanism. People with lots of neurotransmitters bumping around in their heads are not happier than people with few neurotransmitters. Depressed people do not in general have low neurotransmitter levels in the first place. Putting extra serotonin in the brain does no immediate good at all; if you get people to eat more tryptophan (it is found in a number of foodstuffs, including turkey, bananas, and dates), which raises serotonin levels, that doesn’t help immediately, though there is evidence that reducing dietary tryptophan may exacerbate depression. The current popular focus on serotonin is at best naive. As Steven Hyman, director of the National Institute of Mental Health, said rather dryly, “There’s too much serotonin soup and not enough modern neuroscience. We’re not organizing Serotonin Appreciation Day around here just yet.” Under ordinary circumstances, serotonin is discharged by neurons and then reabsorbed to be discharged again. The SSRIs (selective serotonin reuptake inhibitors) block the reabsorption process, thus increasing the level of free-floating serotonin in the brain. Serotonin is one of nature’s through lines in the development of species: it can be found in plants, in lower animals, and in human beings. It appears to serve multiple functions, which vary from one species to the next. In human beings, it is one of several mechanisms that control constriction and dilation of blood vessels. It helps form scabs, causing the clotting necessary to control bleeding. It is involved in inflammatory responses. It also affects digestion. It is immediately involved in regulation of sleep, depression, aggression, and suicide.

  Antidepressants take a long time to cause palpable changes. Only after two to six weeks will the depressed patient experience any real result from his shifted neurotransmitter levels. This suggests that the improvement involves parts of the brain that respond to changed levels of neurotransmitters. Many theories are in circulation, none of which is definitive. The most fashionable until fairly recently was receptor theory. The brain has a number of receptors for each neurotransmitter. When there is more of the transmitter, the brain needs fewer receptors because the transmitter floods all the existing ones. When there is less of the transmitter, the brain needs more receptors to soak up every bit of available neurotransmitter. So increasing the amount of neurotransmitters would cause the number of receptors to go down and might allow the cells that had been acting as receptors to respecialize and take on other functions. Recent research reveals, however, that receptors do not take a long time to respecialize; in fact, they may alter within half an hour of a shift in neurotransmitter levels. So, receptor theory does not explain the time lag experienced with antidepressants. Still, many researchers hold to the notion that some kind of gradual change in brain structure accounts for the delayed response to antidepressants. The effect of the drugs is probably indirect. The human brain is stupefyingly plastic. Cells can respecialize and change after a trauma; they can “learn” entirely new functions. When you raise serotonin levels and cause certain serotonin receptors to close up shop, other things happen elsewhere in the brain, and those downstream things must correct the imbalance that caused you to feel bad in the first place. The mechanisms, however, are completely unknown. “There’s the immediate action of the medication, which leads to some black box we don’t know anything about, which leads to a cure,” says Allan Frazer, chairman of the Department of Psychopharmacology at the University of Texas in San Antonio. “You get the same kind of results from raising serotonin that you get from raising norepinephrine. Do they lead into two different black boxes of function? Do they lead into the same black box? Does one thing lead to the other which leads to a black box?”

  “It’s like putting a grain of sand in an oyster,” Steven Hyman says of antidepressant medication, “and it turns into a pearl. It’s in the adaptations to altered neurotransmitters that slowly, over many weeks, the therapeutic effect occurs.” Elliot Valenstein, at the University of Michigan, adds, “Antidepressants are pharmacologically specific, but not behaviorally specific. The chemistry of products is ever more specific, but God knows what’s really happening in the brain.” William Potter, who was running the psychopharmacological side of the NIMH through the seventies and eighties and has now gone to Eli Lilly to work on the development of new drugs, explains it this way: “There are multiple mechanisms that produce antidepressant effects; drugs with acutely different spectrums of biochemical activity actually have
very similar effects. They converge in ways you would never have expected. You can get pretty much the same antidepressant effects through the serotonin or norepinephrine systems, and in some people, through dopamine. It’s not simple; it’s like a weather system. You do something somewhere that changes wind speeds or humidity, and you get a completely different kind of weather, but how which change will affect what, even the best meteorologists can’t be sure.” Does it matter that most antidepressants suppress REM sleep, or is that an irrelevant side effect? Is it important that antidepressants usually lower brain temperature, which, in depression, tends to go up at night? It has become clear that all the neurotransmitters interact and that each influences the others.

  Animal models are imperfect, but useful information can be gained from animal studies. Monkeys separated from their mothers in infancy grow up psychotic; their brains become physiologically different and they develop much lower serotonin levels than do monkeys raised with their mothers. Repeated maternal separations in a range of animals give them excessive levels of cortisol. Prozac will reverse these effects. Put the dominant male from one colony of marsupials into another grouping in which he is not dominant, and he will go through weight loss, lowered sexual performance, disrupted sleep, and all the other characteristic symptoms of major depression. Raise his serotonin levels and he may well have a total remission of these symptoms. Animals with low serotonin tend to brutalize other animals; they take unnecessary and irrational risks and are confrontational without reason. Animal models of external factors and serotonin levels are extremely revealing. A monkey who rises through the dominance structure of his peer group will show higher levels of serotonin when his rank increases—and high serotonin is associated with lower levels of aggression or suicide. If such monkeys are isolated so that they do not have group status, their serotonin will fall by as much as 50 percent. On selective serotonin reuptake inhibitors (SSRIs), they become less aggressive and less prone to self-destructive activity.

  Four classes of antidepressant medication are currently available. The most popular are the SSRIs, which bring about higher brain levels of serotonin. Prozac, Luvox, Paxil, Zoloft, and Celexa are all SSRIs. There are also two older kinds of antidepressants. The tricyclics, named for their chemical structure, affect serotonin and dopamine. Elavil, Anafranil, Norpramin, Tofranil, and Pamelor are all tricyclics. The monoamine oxidase inhibitors (MAOIs) inhibit the breakdown of serotonin, dopamine, and norepinephrine. Nardil and Parnate are both MAOIs. Another category, atypical antidepressants, includes drugs that operate on multiple neurotransmitter systems. Asendin, Wellbutrin, Serzone, and Effexor are all atypical antidepressants.

  The choice of which medication to use is usually based, at least initially, on side effects. It is hoped that we will eventually find a way to test for responsiveness to specific drugs, but so far we are completely unable to do so. “There is little scientific basis for choosing a particular antidepressant for a particular patient, with a few exceptions,” Richard A. Friedman of Cornell’s Payne-Whitney Hospital says. “Prior response to a given drug is a good predictor of future response to the same drug. And if you have a special subtype of depression, atypical depression, where you overeat and oversleep, you’ll do better on an MAOI than on a tricyclic, though most clinicians use the newer drugs in these patients anyway. Aside from that—you choose a drug that appears to have a low side-effect profile as the first line of action. You can decide on a more activating drug such as Wellbutrin for someone who is very withdrawn, or a deactivating drug for someone who is agitated, but beyond that—it’s just trial and error with the individual patient. The labeling will tell you that one drug has more frequency of certain side effects than another, but in my clinical experience there really isn’t much difference within a particular class in overall levels of side effect from drug to drug. The differences in response at the individual level, however, may be very pronounced.” The great current popularity of the SSRIs—the Prozac revolution—is due not to superior efficacy but to their low side-effect profile and their safety. It’s almost impossible to commit suicide with these drugs, and this is an important consideration in treating depressed people, who may, as they recover, become self-destructive. “Prozac is a very forgiving drug,” says one scientist at Eli Lilly. Decreased side effects mean not only that people will more readily take the drug, but also that they will comply with their regimens better. It’s the same as the principle that if your toothpaste tastes good, maybe you’ll brush longer.

  Some people experience upset stomach with the SSRIs, and there have been occasional reports of headaches, of feeling strung out, of insomnia, and of somnolence. Their major side effect, however, is their undermining of sexuality. “When I was on Prozac,” Brian D’Amato, a depressive friend said to me, “Jennifer Lopez could have appeared at my bedside in a sarong and I’d have asked her whether she could help me with filing.” The tricyclics and MAOIs also have negative sexual side effects; because those drugs, while they dominated the market until the late 1980s, tend to be used only for more severe depression, beside which sexual side effects seem insignificant, their diminishing of erotic pleasure has not been discussed so much and so broadly as that of the SSRIs has been. In studies at the time Prozac was launched, a limited number of patients reported that Prozac was having negative sexual effects. In subsequent studies, when patients were specifically asked about sexual problems, an overwhelming number of them reported difficulties. Anita Clayton, of the University of Virginia, divides sexual experience into four phases: desire, arousal, orgasm, and resolution. Antidepressants affect all four. Desire is compromised by decreased libido. Arousal is diminished by inhibited sexual excitement, diminished genital sensation, impotence, or lack of vaginal lubrication. Orgasm is delayed; some people become totally anorgasmic. Confusingly, these effects can be irregular: one day everything goes fine, and the next day there’s crippling impotence, and you can’t tell which way it’s going to be until you’re in the act itself. Resolution is of course rather undermined when there has been no desire or arousal or orgasm.

  The sexual side effects are often brushed aside as insignificant compared to a severe depression, and by that standard they are insignificant. Nonetheless, they are unacceptable. One patient I interviewed said that he could not have an orgasm in intercourse at all and described the complicated process of going off medication for long enough to impregnate his wife. “If I didn’t know how awful the consequences of being off medication might be,” he said, “I’d have stayed off it. Oh, my sexual self—it was so nice to have it back for a few days. I wonder whether I’ll ever have an orgasm with my wife again.” When you’re first recovering from a depressive episode, when you’ve got other things on your mind, sexual deficiency is not so bothersome, but then to get over unbearable pain at the cost of erotic pleasure—well, it sure struck me as a bum deal. It is also a motivation for noncompliance, which is probably the single biggest problem in the treatment of depression. Less than 25 percent of patients who take antidepressants continue the treatment for six months, and a large proportion of those who stop do so because of sexual and sleep-related side effects.

  Once the sexual effects set in, sexual anxiety ensues, so that erotic encounters may become disturbing moments of failure; people afflicted with this burden may develop a psychological aversion to sexual interaction, which makes the symptoms worse. Most men who have impotence problems suffer from depression; lifting the impotence may be sufficient to reverse the depression. It is both important and difficult, as Clayton has observed, to tease out the sexual problems that are characteristic of the underlying psychology that may have made a person depressed; the sexual problems that are a result of the depression (99 percent of people with acute major depression report sexual dysfunction); and the sexual problems that are the result of antidepressant therapy. Clayton stresses the need for nonintrusive but rigorous scanning of patients for sexual problems.

  Many substances are said to help contravene the se
xual side effects of antidepressants: serotonin antagonists such as cyproheptadine and granisetron; alpha-2 antagonists such as yohimbine and trazodone; cholinergic agonists such as bethanechol; dopamine-enhancing drugs such as bupropion, amantadine, and bromocriptine; autoreceptor agonists such as buspirone and pindolol; stimulants such as amphetamine, methylphenidate, and ephedrine; and herbals such as ginkgo biloba and L-arginine. Taking brief holidays—usually about three days—from drugs achieves occasional positive results. Sometimes switching drugs helps improve libido. None of these have been proved to work particularly well; but they do have some effect, varying from person to person. One woman whose story is told in this book had an alarming experience when she was put on a constellation of these drugs including Dexedrine: she was having such acute libido overflow that she found it physically uncomfortable to sit through routine meetings in her office. Things got to the point that, contrary to her usual habit, she was having sex with strangers in elevators. “I could come three times between the eighth and fourteenth floors,” she told me. “I stopped wearing underwear because it took too long to get it off. The guys thought they were doing something amazing—it was pretty uncomfortable for me, but I feel I really helped some male egos. But it just couldn’t go on. I’m basically a highly repressed WASP. I’m not so young. I really wasn’t up for all this.” Some minor readjustments brought her back to a manageable level of sexual excitation. Unfortunately, the same drugs used on another patient I knew failed to do anything at all for her—“I couldn’t have an orgasm if I got stuck in an elevator for four hours with the young Montgomery Clift,” she sadly reported back to me.